Ventriculoperitoneal shunts in non-HIV cryptococcal meningitis

Cryptococcus neoformans is an opportunistic pathogen and is an important cause of fungal meningitis associated with high morbidity and mortality rates. It commonly occurs in immunosuppressed patients with HIV infections or transplant conditioning, as well as in previously healthy individuals [1, 2]. There are many patients without a severe immunocompromising illness before the development of cryptococcal meningitis (CM) who have a negative HIV test result. Non-HIV related cryptococcosis is becoming a more significant subpopulation in the developed world, accounting for approximately one-third of cases [3]. Therefore, an increased recognition of CM in immunocompetent hosts has begun to direct more attention towards this infection [4]. Persistent and uncontrollable intracranial hypertension (ICH) is a severe complication in patients with CM and is closely related to the count of Cryptococcus. Delays in treatment of ICH are directly related to poor outcomes, including severe headache, papilledema, loss of vision and hearing, and disturbances in consciousness [5]. ICH is an important risk factor for neurological deficits in CM patients and is associated with early death [6, 7]. It has been documented that reducing ICH to normal levels is essential to improving CM patients’ prognosis [6, 8]. Many researchers have previously shown that ventriculoperitoneal shunt (VPS) placement in HIV-infected patients with ICH can result in a good response and a positive outcome [9‐11]. In HIV-related CM patients, the uncontrollable ICH could be relieved by VPS [12]. Nevertheless, few studies have examined VPS in non-HIV CM patients. Some researchers have suggested that the effects of VPS in CM patients with hydrocephalus were limited and that this treatment could not be used effectively in comatose patients [7]. However, Po-Chou Liliang et al. proposed that uncontrollable ICH in non-HIV CM patients without ventriculomegaly could be resolved by the use of VPS, and the patients’ neurological deficits could be improved [13]. Hence, the proposed role of VPS in non-HIV CM patients has also been inconsistent.

Here, our study offers a retrospective review to analyse the difference after VPS between non-HIV CM patients with and without ventriculomegaly. We conducted this study to assess the predictive value of the response to VPS in non-HIV CM patients. An additional aim was to evaluate whether there were differences in the effects of VPS in CM patients with and without ventriculomegaly.

CM is the most common fungal meningitis in HIV-positive patients. In the absence of HIV, CM patients with underlying immune dysfunction, such as organ transplantation, corticosteroid medication use and malignancy, account for the majority of cases. In our study, we found that liver disease, diabetes mellitus, malignancy, pulmonary cryptococcosis and autoimmune diseases were the major underlying diseases. These findings had some similar features to a previous study in HIV-negative patients [16, 17] but also showed some differences. In our study, we found that in the VPSV group, 5 of the 13 (38.5%) patients suffered from liver diseases. Five patients (38.5%) had no apparent underlying disease. In the VPSWOV group, 3 of the 10 patients (30%) had pulmonary cryptococcosis. Two patients (20%) had no apparent underlying disease. The male sex was predominant in both groups. VPSWOV patients were obviously older than VPSV, and people with VPSWOV tended to receive surgical treatment earlier, making the symptom duration shorter.

Uncontrollable ICH, a severe complication in patients with CM, is defined as a CSF opening pressure > 250 mmH₂O and is generally considered to relate to high fungal burden in the CSF [18]. Symptoms include headache, papilledema, vomiting, vision and hearing loss, and impaired mentation. Our study showed that headache, vomiting, fever and loss of vision were the most common clinical features in both the VPSV and VPSWOV groups. Headache could continue to ease after VPS operation. On the other hand, impaired eyesight and hearing, as well as altered mental status, were not improved significantly.

An elevated CSF pressure level is significantly linked to increased mortality and poor outcomes [19, 20]. The goal of CM treatment is to reduce fungal burden and to prevent long-term neurological deficits. The decompression is a very important parameter in this management. Ventriculomegaly is an uncommon complication of CM patients. There are multiple treatments to control ICP such as medications, repeated LP, temporary external drainage or permanent VPS [15]. For CM patients with progressive ventriculomegaly, VPS is a favoured method of diversion to relieve the ICH, which is well studied in HIV-positive [10, 21] and HIV-negative [7, 11] CM patients. However, relevant articles about VPS treatment in non-HIV patients without ventriculomegaly are limited. Available data are limited to case reports [13] and smaller case studies [22]. Comparative data concerning the non-HIV CM population with and without ventriculomegaly are sparse. Here, we present a comprehensive analysis of clinical, CSF characteristics and prognosis in both groups in order to further assess the roles of VPS in non-HIV CM patients.

The mechanisms of the development of elevated ICP with ventriculomegaly in CM are complex. Some reports have shown the following possible pathogenesis pathways: (1) the channels for CSF drainage may be blocked by fungal polysaccharides, or (2) the passage of CSF across the arachnoid villi may be blocked by an inflammatory response [23]. For those CM patients with ICH but without ventriculomegaly, previous research has suggested that (1) deposits of cryptococcal capsular polysaccharides on the brain surface and within the parenchyma tissue could lead to the brain’s inability to respond to the increased CSF volume and pressure [7, 24]. (2) The venous stenosis may limit cerebral blood outflow due to an infection-mediated mechanism [21]. In brief, ICH is closely associated with fungal overload. In our study, by comparing the pre-operation CSF characteristics, we found that a higher Cryptococcus count was observed in the VPSWOV group than in the VPSV group via India ink staining tests. There was no significant difference found in CSF cell counts or protein, glucose or chloride levels between the two groups. When compared with pre-operation levels, we found that the CSF pressure in both groups and fungal count in the VPSV group were significantly decreased within 1 week after the operation. Moreover, we presented the status when patients were discharged from hospital and when they returned to hospital after 1 month. Interestingly, we see similar results at these two observation time points. There were significantly decreased ICH and fungal loads after VPS in both the VPSV and VPSWOV groups. VPS helped to reduce ICH and fungal load. However, our results suggest patients would have poor outcomes if they have a serious underlying disease.

Continuous ICH, in CM patients both with and without ventriculomegaly, can lead to irreversible neurological complications and increase morbidity and mortality. Failure to address the consequences of ICH would be significantly detrimental. If the initial treatment, even combined with appropriate antifungal therapy, still fails to control ICH, VPS could be an effective choice. Our study has shown that CSF pressure and Cryptococcus counts were significantly decreased after VPS, and headache could continue to improve.

In summary, our data suggest that early placement of a VPS is helpful in decreasing uncontrollable ICH and fungal overload, regardless of the ventriculomegaly status of non-HIV CM patients. The VPS could not only relieve the symptoms of ICH, but could also improve the clinical features of CM patients. Therefore, early diagnosis and early use of VPS in CM patients, before the onset of severe neurological deficit symptoms, could be beneficial and essential. We look forward to future clinical studies to confirm this result.